title: Anaesthetic impairment of immune function is mediated via GABA(A) receptors.
abstract: BACKGROUND
  GABA(A) receptors are members of the Cys-loop family of neurotransmitter receptors, proteins which are responsible for fast synaptic transmission, and are the site of action of wide range of drugs. Recent work has shown that Cys-loop receptors are present on immune cells, but their physiological roles and the effects of drugs that modify their function in the innate immune system are currently unclear. We are interested in how and why anaesthetics increase infections in intensive care patients; a serious problem as more than 50% of patients with severe sepsis will die. As many anaesthetics act via GABA(A) receptors, the aim of this study was to determine if these receptors are present on immune cells, and could play a role in immunocompromising patients.
  
  
  RESULTS
  We demonstrate, using RT-PCR, that monocytes express GABA(A) receptors constructed of α1, α4, β2, γ1 and/or δ subunits. Whole cell patch clamp electrophysiological studies show that GABA can activate these receptors, resulting in the opening of a chloride-selective channel; activation is inhibited by the GABA(A) receptor antagonists bicuculline and picrotoxin, but not enhanced by the positive modulator diazepam. The anaesthetic drugs propofol and thiopental, which can act via GABA(A) receptors, impaired monocyte function in classic immunological chemotaxis and phagocytosis assays, an effect reversed by bicuculline and picrotoxin.
  
  
  CONCLUSIONS
  Our results show that functional GABA(A) receptors are present on monocytes with properties similar to CNS GABA(A) receptors. The functional data provide a possible explanation as to why chronic propofol and thiopental administration can increase the risk of infection in critically ill patients: their action on GABA(A) receptors inhibits normal monocyte behaviour. The data also suggest a potential solution: monocyte GABA(A) receptors are insensitive to diazepam, thus the use of benzodiazepines as an alternative anesthetising agent may be advantageous where infection is a life threatening problem.
authors.affiliation: Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Wheeler
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Federico
authors.initials: F
authors.lastname: Corletto
authors.forename: Jill
authors.initials: J
authors.lastname: Reckless
authors.forename: Justin C T
authors.initials: JC
authors.lastname: Loke
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lapaque
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grant
authors.forename: Pietro
authors.initials: P
authors.lastname: Mastroeni
authors.forename: David J
authors.initials: DJ
authors.lastname: Grainger
authors.forename: Claire L
authors.initials: CL
authors.lastname: Padgett
authors.forename: John A
authors.initials: JA
authors.lastname: O'Brien
authors.forename: Nigel G A
authors.initials: NG
authors.lastname: Miller
authors.forename: John
authors.initials: J
authors.lastname: Trowsdale
authors.forename: Sarah C R
authors.initials: SC
authors.lastname: Lummis
authors.forename: David K
authors.initials: DK
authors.lastname: Menon
authors.forename: John S
authors.initials: JS
authors.lastname: Beech
mesh_terms: D000777:Anesthetics / Q000009:adverse effects* / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D002460:Cell Line; D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D006801:Humans; D007107:Immune System / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007154:Immune System Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D016867:Immunocompromised Host / Q000187:drug effects / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D009118:Muscimol / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D000777:Anesthetics; D001640:Bicuculline; D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D009118:Muscimol; D010852:Picrotoxin; D011963:Receptors, GABA-A